Inhibition of DNA synthesis in P388 lymphocytic leukemia cells of BDF1 mice by cis-diamminedichloroplatinum(II) and its derivatives.
cis-Diamminedichloroplatinum(II) (cisplatin; cDDP) derivatives were found to afford T/C% values greater than 200 against the growth of P388 lymphocytic leukemia cells in vivo. The parent compound, cDDP, preferentially inhibited DNA synthesis. The RNA synthesis was elevated, whereas protein synthesis was unaffected after two or three daily ip doses. Radiolabeled drug studies demonstrated cellular uptake and binding of cDDP derivatives to the DNA molecule. cis-Diamminedichloroplatinum(II) (cDDP) treatment resulted in DNA strand scission after a single dose, but caused cross-linking of DNA strands after two or three ip doses. There was an accumulation of deoxynucleoside triphosphates [d(NTP)s] on day 2 and 3, indicating that incorporation of nucleotides into the DNA strand had been blocked. Thymidine kinase, thymidine monophosphate kinase, carbamoyl phosphate synthetase, and aspartate transcarbamoylase activities were inhibited in vivo after three doses of cDDP at 1.5 mg/kg/day. However, only the inhibition of a cytoplasmic preparation of DNA polymerase alpha by cDDP appeared to be directly related to the inhibition of DNA synthesis and the accumulation of d(NTP) pool levels. Thus, the primary target for cDDP appears to be DNA itself, although direct inhibition of DNA polymerase alpha may play a minor role in the inhibition of DNA replication by cDDP.
Oswald
C B
CB
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill 27599.
Chaney
S G
SG
Hall
I H
IH
D000818:Animals; D002945:Cisplatin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D004257:DNA Polymerase II / Q000378:metabolism; D004273:DNA, Neoplasm / Q000096:biosynthesis* / Q000187:drug effects; D007941:Leukemia P388 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009363:Neoplasm Proteins / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D013347:Subcellular Fractions / Q000201:enzymology / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; D004257:DNA Polymerase II; D002945:Cisplatin